US20090042820A1 - Tubulin Binding Anti Cancer Agents And Prodrugs Thereof - Google Patents

Tubulin Binding Anti Cancer Agents And Prodrugs Thereof Download PDF

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US20090042820A1
US20090042820A1 US11/791,420 US79142005A US2009042820A1 US 20090042820 A1 US20090042820 A1 US 20090042820A1 US 79142005 A US79142005 A US 79142005A US 2009042820 A1 US2009042820 A1 US 2009042820A1
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alkylamino
hydrogen
compound
aryl
alkoxy
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Mark Matteucci
Jian-Xin Duan
Xiaohong Cai
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Molecular Templates Inc
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Threshold Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention provides compositions and methods for treating cancer and other hyperproliferative disease conditions and generally relates to the fields of chemistry, biology, molecular biology, pharmacology, and medicine.
  • the present invention provides tubulin binding compounds and their prodrugs for treating cancer and other hyperproliferative disease conditions.
  • Tubulin-containing structures such as microtubules are important for diverse cellular functions, including chromosome segregation during cell division, intracellular transport, development and maintenance of cell shape, cell motility, and possibly distribution of molecules on cell membranes (Bacher et al., Pure Appl. Chem., 73(9): 1459-1464, 2001).
  • Precipitation and sequestration of tubulin structure interrupts many important biological functions that depend on tubulin via the microtubular class of subcellular organelles. For example, inhibition of tubulin polymerization or prevention of the disassembly of tubulin polymer causes cell cycle arrest which ultimately leads to cell death. As a result, tubulin is a promising target in cancer therapy.
  • Drug compounds that interfere with tubulin can be useful anti-cancer agents.
  • Three important binding domains have been identified on tubulin where such drug compounds can bind.
  • These drugs have diverse chemical structure (Angerer et al., Curr. Opin. Drug Discov. Dev., 2000, 3(5): 575-584 incorporated herein by reference) suggesting that they can bind on different regions of tubulin.
  • Angerer et al., Curr. Opin. Drug Discov. Dev., 2000, 3(5): 575-584 incorporated herein by reference suggesting that they can bind on different regions of tubulin.
  • a common outcome of tubulin binding of these drugs is that they cause precipitation and sequestration of tubulin.
  • Clinically used anti-cancer drugs targeting tubulin are of natural origin, namely, the taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinblastine, vinorelbine), and podophyllotoxins/colchicine. These agents either inhibit polymerization of tubulin (vinca alkaloids/colchicine) or prevent disassembly of microtubules (taxanes). More recently, the natural products epothilone A and B and their analogs were found to be stabilizers of microtubules and highly cytotoxic.
  • tubulin-targeting drugs are used clinically to treat cancer, they have several disadvantages (see Bacher et al., supra).
  • the complex chemical structures of these representative drugs make their synthesis difficult and isolating them from natural resources is often difficult.
  • Another major drawback in clinical application of taxanes and vinca alkaloids is the development of neurotoxicity. These drugs interfere with the function of microtubules in axons, which mediate the neuronal vesicle transport. The insolubility of some of these drugs makes administration difficult. Further, over-expression of transmembrane pumps results in development of drug resistance to these agents. These factors limit the potential of these natural products.
  • Combretastatin A is a small-molecular weight natural product which binds to the colchicine binding part of tubulin and inhibits tubulin polymerization.
  • Administration of Combretastatin A is problematic because of its low aqueous solubility.
  • a water soluble phosphate prodrug of Combretastatin A is used in therapy.
  • the phosphate group is hydrolyzed by phosphatases that are not tumor specific, to yield Combretastatin A. Release of insoluble Combretastatin A away from the tumor following such hydrolysis can cause administration problems.
  • anti-cancer compounds preferably tubulin binding anti-cancer compounds, especially those that are not substrates of transmembrane pumps and/or do not interfere with the function of axonal microtubules and/or provide an increased therapeutic index in the treatment of cancer.
  • the present invention meets these needs.
  • the present invention provides a compound having a formula selected from:
  • each Q 1 , Q 2 , and Q 6 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 15 ; SO 2 R 15 ; or PO 3 R 15 ;
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 or PO 3 R 15 with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl;
  • Q 7 is hydrogen; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 18 ; SO 2 R 15 ; PO 3 R 15 or a monosaccharide; with the proviso that in formula (II) Q 7 excludes hydrogen;
  • Q 8 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 or PO 3 R 15 ;
  • each Q 9 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 or PO 3 R 15 ;
  • X is O, —NNHR 16 , NR 16 , or NOR 16 ;
  • Y is hydrogen, hydroxyl, or halogen
  • Z is —CH— or —N—
  • R 15 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • R 16 is hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, C 1 -C 6 alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 acyl, aroyl, aminothiocarbonyl, C 1 -C 6 alkylaminothiocarbonyl, di C 1 -C 6 alkylaminothiocarbonyl, C 1 -C 6 thioacyl, or thioaroyl; with the proviso that when X is NR 16 , R 16 excludes hydrogen;
  • R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • the compounds are tubulin binding compounds.
  • the present invention provides a compound of formula (XXI)-(XXVII):
  • each Q 1 , Q 2 , and Q 6 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 18 ; SO 2 R 18 ; or PO 3 R 15 ;
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 ; or PO 3 R 18 with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • Q 7 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 15 ; SO 2 R 18 ; or PO 3 R 18 or a monosaccharide; with the proviso that in formula (II) Q 7 excludes hydrogen;
  • Q 8 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 or PO 3 R 18 ;
  • each Q 9 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 or PO 3 R 18 ;
  • V is —NHR 16 ; —NHNHR 16 ; —NHN(R 16 ) 2 ; —NR 16 NHR 16 ; or —OR 17 ;
  • Y is hydrogen, hydroxyl or halogen
  • Z is —CH— or —N—
  • R 15 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 cycloalkyl, C 1 -C 6 heterocyclyl, aryl, or heteroaryl;
  • R 16 is hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, C 1 -C 6 alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 acyl, aroyl, aminothiocarbonyl, C 1 -C 6 alkylaminothiocarbonyl, di C 1 -C 6 alkylaminothiocarbonyl, C 1 -C 6 thioacyl, or thioaroyl; and R′ is C 1 -C 6 alkyl or aryl; with the proviso that when V is NR 16 , R 16 excludes hydrogen;
  • R 17 is C 1 -C 6 alkyl; aryl; or di C 1 -C 6 alkylamino;
  • R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • these compounds are tubulin binding compounds.
  • the present invention provides prodrug compounds wherein the novel compound of the invention is bonded to a hypoxic activator (-Hyp) through a hydroxyloxygen (-OHyp) or an amine nitrogen (-NHyp) in the tubulin binding compound.
  • a hypoxic activator -Hyp
  • -OHyp hydroxyloxygen
  • -NHyp amine nitrogen
  • the present invention provides prodrug compounds of known tubulin binding anti-cancer compounds wherein the tubulin binding compound is bonded to the hypoxic activator (Hyp) through an hydroxyl oxygen (-OHyp) or an amine nitrogen (-NHyp) in the tubulin binding compound.
  • Hyp hypoxic activator
  • -OHyp hydroxyl oxygen
  • -NHyp amine nitrogen
  • the hypoxic activator can be nitrobenzene moieties, nitrobenzoic acid amide moieties, nitroazole moieties, nitroimidazole moieties, nitrothiophene moieties, nitrothiazole moieties, nitrooxazole moieties, nitrofuran moieties, and nitropyrrole moieties.
  • Hyp is selected from:
  • each X 2 is N or CR 32 ;
  • X 3 is NR 31 , S, or O;
  • each R 30 is independently hydrogen or alkyl
  • R 31 is hydrogen, hydroxyl, C 1 -C 6 alkyl or heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aryl or heteroaryl, C 1 -C 6 acyl or heteroacyl, aroyl, or heteroaroyl;
  • R 32 is hydrogen, halogen, nitro, cyano, CO 2 H, C 1 -C 6 alkyl or heteroalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aryl, CON(R 7 ) 2 , C 1 -C 6 acyl or heteroacyl, or aroyl or heteroaroyl; and
  • n 0, 1.
  • Hyp is selected from
  • hypoxic activator is a substituted or unsubstituted nitroimidazole moiety.
  • Hyp is
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a novel compound or a novel prodrug compound of the invention.
  • the present invention provides a method of treating cancer comprising administering a therapeutically effective amount of a novel compound or a novel prodrug compound of the invention alone or in combination with one or more other anti-cancer agents to a subject in need of such treatment.
  • FIG. 1 illustrates graphically the time course of mice bodyweight recorded during the experiment in the three groups.
  • FIG. 2 illustrates graphically the time course tumor volume recorded during the experiment in the three groups.
  • C 1 -C 6 alkyl or (C 1 -C 6 ) alkyl refers to substituted or unsusbstituted straight or branched chain alkyl groups having 1-6 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.
  • a C 1 -C 6 alkyl substituent may be covalently bonded to an atom within a molecule of interest via any chemically suitable portion of the C 1 -C 6 alkyl group.
  • “C 1 -C 6 alkyl” or (C 1 -C 6 ) alkyl may be further substituted with substituents, including for example, hydroxy, amino, mono or di(C 1 -C 6 )alkyl amino, halogen, C 2 -C 6 alkyl ether, cyano, nitro, ethenyl, ethynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio,
  • Substituted C 1 -C 6 alkyl groups include, for example, —CH 2 —CH 2 —OH, —CH 2 —CH 2 -halogen, —CH 2 —CH 2 —NH 2 , —CH 2 —CH 2 —O—CH 2 —CH 2 —OH, —CH 2 —CH 2 —CH 2 —NH—CH 2 —CH 2 —OH and —CH 2 —CH 2 —NH—CH 2 —CH 2 —OH and the like.
  • Cycloalkyl refers to a monovalent cyclic hydrocarbon radical of three to seven ring carbons.
  • the cycloalkyl group may have double bonds which may but not necessarily be referred to as “cycloalkene” or “cycloalkenyl”.
  • the cycloalkyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, —COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl),
  • n is an integer from 0 to 5
  • R′ and R′′ are independently hydrogen or alkyl
  • R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl
  • —(CR′R′′) n —CONR x R y where n is an integer from 0 to 5, R′ and R′′ are independently hydrogen or alkyl, R x and R y are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).
  • cycloalkyl includes, for example, cyclopropyl, cyclohexyl, cyclohexenyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2-carboxamido-cyclohexenyl, 2-dimethylaminocarbonyl-cyclohexyl, and the like.
  • Heteroalkyl means an alkyl radical as defined herein with one, two or three substituents independently selected from cyano,
  • R w is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- or di-alkylcarbamoyl.
  • R x is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or araalkyl.
  • R y is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, mono- or di-alkylcarbamoyl or alkylsulfonyl.
  • R z is hydrogen (provided that p is 0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, amino, mono-alkylamino, di-alkylamino, or hydroxyalkyl.
  • R w , R x , R y , and R z can be further substituted by amino, fluorine, alkylamino, di-alkylamino, OH or alkoxy.
  • the prefix indicating the number of carbon atoms refers to the total number of carbon atoms in the portion of the heteroalkyl group exclusive of the cyano, —OR w , —NR x R y , or —S(O) p R z portions.
  • heteroalkyl by itself or in combination with another term, also refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • Examples include, but are not limited to, —CH 2 —CH 2 —O—CH 3 , —CH 2 —CH 2 —NH—CH 3 , —CH 2 —CH 2 —N(CH 3 )—CH 3 , —CH 2 —S—CH 2 —CH 3 , —CH 2 —CH 2 —S(O)—CH 3 , —CH 2 —CH 2 —S(O) 2 —CH 3 , —CH ⁇ CH—O—CH 3 , —Si(CH 3 ) 3 , —CH 2 —CH ⁇ N—OCH 3 , and —CH ⁇ CH—N(CH 3 )—CH 3 .
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH 2 —CH 2 —S—CH 2 —CH 2 — and —CH 2 —S—CH 2 —CH 2 —NH—CH 2 —.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O) 2 R′— represents both —C(O) 2 R′- and —R′C(O) 2 —.
  • heterocycle means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one to four ring atoms are heteroatoms selected from O, NR (where R is independently hydrogen or alkyl) or S(O) p (where p is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group.
  • the heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, —COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), —(CR′R′′) n —COOR (n is an integer from 0 to 5, R′ and R′′ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or —(CR′R′′) n —CONR
  • heterocyclyl includes, but is not limited to, pyridyl, tetrahydropyranyl, N-methylpiperidin-3-yl, N-methylpyrrolidin-3-yl, 2-pyrrolidon-1-yl, furyl, quinolyl, thienyl, benzothienyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyran-4-yl, tetrahydroimidazo[4,5-c]pyridinyl, imidazolinyl, piperazinyl, and piperidin-2-onyl.
  • R x and R y together is heterocyclyl. More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted forms thereof.
  • C 1 -C 6 alkoxy means a substituted or unsubstituted alkyl group of 1 to 6 carbon atoms covalently bonded to an oxygen atom.
  • a C 1 -C 6 alkoxy group has the general structure —O—(C 1 -C 6 alkyl) wherein alkyl is as described above.
  • C 1 -C 6 alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • C 1 -C 6 alkoxycarbonyl refers to an alkoxy group covalently bonded to a carbonyl.
  • a C 1 -C 6 alkoxycarbonyl group has the general structure —C( ⁇ O)—O—(C 1 -C 6 )alkyl wherein alkyl is as described above.
  • C 1 -C 6 alkylamino means a substituted or unsubstituted alkyl group of 1 to 6 carbon atoms covalently bonded to —NH—.
  • a C 1 -C 6 alkylamino group has the general structure —NH—(C 1 -C 6 )alkyl wherein alkyl is as described above.
  • C 1 -C 6 alkylamino groups include, for example, methylamino, ethylamino, propylamino and butylamino.
  • C 2 -C 6 alkyl ether refers to an ether substituent with 2 to 6 carbon atoms, positioned such that at least one carbon atom is located on either side of the oxygen atom.
  • aryl refers to substituted or unsusbstituted moieties that include one or more monocyclic or fused ring aromatic systems. Such moieties include any moiety that has one or more monocyclic or bicyclic fused ring aromatic systems, including but not limited to phenyl and naphthyl.
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • heteroaryl refers to substituted or unsusbstituted monocyclic aromatic groups having 5 or 6 ring atoms, or fused ring bicyclic aromatic groups having 8 to 20 atoms, in which the ring atoms are C, O, S, SO, SO 2 , or N and at least one of the ring atoms is a heteroatom, i.e., O, S, SO, SO 2 , or N.
  • Heteroaryl groups include for example acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio-furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, is
  • the arrangement of the hetero atoms within the ring may be any arrangement allowed by the bonding characteristics of the constituent ring atoms.
  • Aryl or heteroaryl groups may be further substituted with substituents, including for example, hydroxy, amino, mono or di(C 1 -C 6 )alkyl amino, halogen, C 2 -C 6 alkyl ether, cyano, nitro, ethenyl, ethynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, —COOH, —CONH 2 , mono- or di-(C 1 -C 6 )alkyl-carboxamido, —SO 2 NH 2 , —OSO 2 —(C 1 -C 6 )alkyl, mono or di(C 1 -C 6 )alkylsulfon-amido, aryl, and heteroaryl.
  • hydroxy(C 1 -C 6 )alkyl refers to a substituted or unsubstituted aliphatic group having from 1 to 6 carbon atoms, and further comprising at least one hydroxyl group on the main carbon chain and/or on a side chain.
  • Hydroxy(C 1 -C 6 )alkyl groups include, for example, —CH 2 —CH 2 —OH and
  • a “protected form of formyl” refers to acetals, oximes, and hydrazones.
  • hypoxic activator or “hypoxia activated trigger” refers to a group or moiety that is capable of releasing another compound, such as an antineoplastic agent or analogs thereof upon hypoxic reduction.
  • the hypoxic activator is a group that is capable of releasing the antineoplastic agent or analogs thereof upon reduction of the hypoxic activator under hypoxic conditions but does not release any antineoplastic agent or analog under normoxic conditions.
  • one hypoxic activator is a nitroimidazole that may be substituted with a variety of groups.
  • hypoxic activators include, but are not limited to, groups based on nitrobenzenes, nitrobenzoic acid amides, nitroazoles, nitroimidazoles, nitrothiophenes, nitrothiazoles, nitrooxazoles, nitrofurans, and nitropyrroles, where each of these classes of moieties may be substituted or unsubstituted, such that the redox potential for the group lies within a range where the group can undergo reduction in the hypoxic regions of a tumor.
  • hypoxic activators are described in Matteucci et al., PCT Publication No. WO 04/087075 and U.S. Pat. Appl. No. 60/695,755 each of which is incorporated herein by reference.
  • nitrothiophene, nitrofuranfuran, and nitrothiazole groups may be substituted with one or more electron donating groups, including but not limited to methyl, methoxy, or amine groups, to provide a hypoxic activator with the desired redox potential.
  • the nitropyrrole moiety can be substituted with an electron withdrawing group, including but not limited to cyano, carboxamide,
  • —CF 3 and sulfonamide groups, to achieve a group with the desired redox potential.
  • strong electron withdrawing groups such as cyano, sulfone, sulfonamide, carboxamide, or —CF 3
  • milder electron withdrawing groups such as —CH 2 -halogen, where halogen is —F, —Cl, or —Br, can be used.
  • a “prodrug” is a compound that, after administration, is metabolized or otherwise converted to an active or a more active compound compared to the corresponding prodrug.
  • a cytotoxic, pharmaceutically active compound or precursor thereof can be modified chemically to render it less active or inactive, but the chemical modification is such that an active form of the compound is generated from the resulting prodrug by metabolic or other biological processes.
  • prodrug synthesis does not necessarily require use of the active drug as synthetic intermediate.
  • a prodrug can have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects, or lower toxicity (for example, see Nogrady, 1985 , Medicinal Chemistry A Biochemical Approach , Oxford University Press, New York, pages 388-392).
  • substituted refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest.
  • substitution refers to replacing a hydrogen atom in a molecular structure with a substituent such that the valence on the designated atom (for example 4 for carbon) is not exceeded, and a chemically stable compound (a compound that can be isolated, characterized, and/or tested for biological activity) results.
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 4° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds of this invention may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of A DVANCED O RGANIC C HEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992).
  • “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
  • Protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T. W. Greene and P. G. Wuts, P ROTECTIVE G ROUPS IN O RGANIC C HEMISTRY , (Wiley, 2nd ed. 1991) and Harrison and Harrison et al., C OMPENDIUM OF S YNTHETIC O RGANIC M ETHODS , Vols. 1-8 (John Wiley and Sons. 1971-1996).
  • Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC) and the like.
  • hydroxy protecting groups include those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • patient typically refers to a human but more generally refers to a mammal.
  • Those of skill in the art will appreciate that the methods and compositions of the invention can be used to treat cancer or other hyperproliferative diseases in any mammal, including non-human primates, and experimental models of human cancers.
  • the patient is a human patient.
  • treating refers to taking steps to obtain beneficial or desired therapeutic results, including clinical results.
  • beneficial or desired therapeutic results include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer, diminishment of extent of disease, delay or slowing of disease progression, palliation or stabilization of the disease state, and other beneficial results, as described below.
  • “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s) or eliminating the symptom(s).
  • administering or “administration of” a drug to a subject (and grammatical equivalents of this phrase) can include direct administration, including self-administration and/or indirect administration, including the act of prescribing a drug.
  • direct administration including self-administration and/or indirect administration, including the act of prescribing a drug.
  • indirect administration including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • an “effective amount” or a “therapeutically effective amount” of a drug is an amount of a drug that, when administered to a subject with cancer or any other hyperproliferative disease condition, will have (i) the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of cancer or other disease in the subject; or (ii) a prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of disease or symptoms or reducing the likelihood of the onset (or reoccurrence) of disease or symptoms.
  • the full therapeutic or prophylactic effect does not necessarily occur by administration of one dose and can occur only after administration of a series of doses.
  • a therapeutically or prophylactically effective amount can be administered in one or more administrations.
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of disease or symptoms, or reducing the likelihood of the onset (or reoccurrence) of disease or symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use. Examples include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like, used in the preparation of a pharmaceutical composition. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions or pharmaceutical formulations of the invention is contemplated. Supplementary active ingredients can be incorporated into the compositions of the invention.
  • a “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.
  • the compounds of the invention can be described in part as compounds which can bind to tubulin, and prodrugs thereof comprising a hypoxic activator.
  • the compounds are anti-cancer compounds which can bind to tubulin, and prodrugs thereof comprising a hypoxic activator.
  • the compounds are synthetic, anti-cancer compounds which can bind to tubulin, and prodrugs thereof comprising a hypoxic activator. While a number of synthetic small-molecule tubulin binding anti-cancer compounds are known, none of them have been approved for cancer therapy. A number of synthetic tubulin binding compounds bind to the colchicine binding region of tubulin, and show structural and functional similarities with colchicine.
  • Colchicine binds to tubulin and interferes with the function of the mitotic spindles causing depolymerization and disappearance of tubulin polymers known as microtubules. Disappearance of microtubules disrupts spindle formation as a result of which Colchicine arrests mitosis in metaphase. Cancer cells with a high rate of cell division are affected by mitotic arrest and high concentrations of Colchicines can completely prevent cells from entering mitosis, resulting in cell death.
  • a Colchicine-like tubulin binder such as Combretastatin A can selectively target the vascular system of tumors.
  • the morphological changes induced in the endothelial cells of the tumor's blood vessels irreversibly shut down the blood flow to cancer cells while leaving the blood supply to healthy cells intact.
  • tubulin binding compounds Colchicine and Combretastatin A indicates that the pharmacophore responsible for their tubulin binding contains two aryl rings functionalized with methoxy and/or hydroxyl groups.
  • a number of di- and tri-aryl compounds having tubulin binding ability have been synthesized (see, for example, Nam et al., Curr. Med. Chem., 2003, 10:1697-1722 and Hsieh et al., US Patent Publication No. 2003/0195244, each of which is incorporated herein by reference).
  • Heterocyclic indole, benzofuran, and benzothiophene containing tubulin binding di- and tri-aryl compounds constitute a sub-class of these compounds (see Nam et al. supra). These compounds, for example, have an aromatic moiety such as an aryl or an aroyl
  • R 1 is CO or CH 2 ;
  • R 3 is H, methyl, aryl or aroyl; and
  • R 2 and R 4 are methyl or OMe.
  • the present invention arises in part out of the unexpected discovery that replacing the aromatic moiety or the CH group with a N atom at the 2-position on the heterocyclic portion of these compounds yields an indazole compound with anticancer activity
  • the corresponding propargylic compound demonstrated about 10 fold higher cancer cell killing ability in an antiproleferation assay, compared to a corresponding compound having Q 1 as H.
  • Compounds of the present invention also arise in part out of the discovery that the proper spatial disposition (i.e. a conformation) between the aryl moieties in the tubulin binding compounds can be stabilized by incorporating a hydrogen bond donor in place of the keto group of the aroyl moiety. As illustrated below, steric repulsion between proximal atoms can move rings A and B from co-planarity. Hydrogen bonding stabilizes the desired conformation of a compound of the present invention in a colchicines-like conformation.
  • a compound of the present invention in one conformation can have a colchicine-like structure; while in other conformations have a non-coichicine like structure. These latter conformations can reduce the effective tubulin binding of the compound.
  • a group which is a hydrogen bond donor the spatial disposition of the aryl groups can be modulated toward a tubulin binding conformation via hydrogen bonding.
  • this invention further provides, an enol ⁇ C(OH)— and a ⁇ C(halogen)-moiety at that position as hydrogen bond acceptors.
  • an —NH— or a ⁇ CH— group at the same position can act as a hydrogen bond donor and stabilize a tubulin binding conformation by hydrogen bonding to a hydrogen bond acceptor suitably disposed in the molecule.
  • the present invention also provides prodrugs of known and novel tubulin binding compounds of this invention.
  • prodrug aspect of the invention an understanding of tumor biology is helpful.
  • Cancer cells generally divide more frequently than normal cells.
  • Tubulin binding-drug mediated cancer therapies include cytotoxic agents selective for dividing cells.
  • tubulin binding compounds target cancer cells, as opposed to normal cells, generally because cancer cells undergo cell division more frequently than normal cells.
  • drugs targeting dividing cells do not kill all of the cancer cells in the solid tumor.
  • cancer cells can acquire mutations that confer drug resistance.
  • Another is that not all cancer cells divide more frequently than normal cells.
  • These slowly-dividing cancer cells are generally located in the hypoxic region of the tumor and can be as, or even more, insensitive to such inhibitors as normal cells. The formation and consequences of the tumor hypoxic region is described below.
  • the new vasculature that supports tumor growth is often disordered, leaving significant regions of the tumor under-vascularized and even the vascularized regions subject to intermittent blockage. Cells in these regions are unable to generate the energy required for cell division. These under-vascularized and blocked regions of the tumor become hypoxic—they have a lower oxygen concentration than the corresponding normal tissue. Thus, the median oxygen concentration of only ten percent of solid tumors falls in the normal range of 40-60 mm Hg, and fifty percent of solid tumors exhibit median oxygen concentrations of less than 10 mm Hg.
  • hypoxic regions of the tumor can constitute a significant reservoir of cancer cells resistant to therapy.
  • low tumor oxygen levels are associated with a poor response to therapy, increased metastases, and poor survival.
  • cancer cells do not divide significantly faster than normal cells, and can be resistant to therapeutic agents such as tubulin binding compounds that target dividing cells.
  • hypoxic region is conducive to biochemical reduction that can be used to generate reduced derivatives of a variety of chemical groups (see Workman et al., 1993 , Cancer and Metast. Rev. 12: 73-82), and prodrugs of cytotoxins can be developed to exploit such hypoxic regions (see, Matteucci et al., PCT Publication No. WO 04/087075).
  • Compounds of the present invention arise in part out of the discovery that, cancer cells in the hypoxic region can be targeted by prodrug compounds comprising a tubulin binding cytotoxin and a hypoxia labile protecting group.
  • the hypoxic cells of the tumor generate the active toxin from the inactive, relatively non-toxic prodrug.
  • the active drug diffuses from the hypoxic cells and kills the cancer cells in adjacent regions, including the more frequently dividing cells.
  • the hypoxic region acts as a drug-factory to produce a cytotoxin within a tumor for killing adjacent normoxic cancer cells leading to a higher concentration of the cytotoxin within the tumor, relative to normal tissues.
  • a prodrug to generate the cytotoxin within the tumor, toxic side-effects arising due to normal cell toxicity can be reduced.
  • a hypoxic region can become normoxic and start dividing.
  • tubulin binding cytotoxins generated from the prodrug compounds of this invention, or by administering compounds of this invention in combination with other cytoxins, including for example, tubulin binding compounds and other anti-cancer cytotoxins.
  • hypoxia activated prodrug when alkylated with N-1-methyl-2-nitro-5-imidazolemethyl group can yield a hypoxia activated prodrug. Under hypoxic conditions the hypoxic activator is reduced and removed yielding the potent toxin.
  • the hypoxic activator can be attached to the nitrogen atoms via a —CO 2 -linker as well as shown schematically below.
  • the present invention also provides novel prodrugs of previously known tubulin binding anti-cancer compounds.
  • the tubulin binding compound is bonded to the hypoxic activator (Hyp) through a hydroxyl oxygen (-OHyp) or an amine nitrogen (-NHyp) in the tubulin binding compound to yield a hypoxia active prodrug.
  • the hypoxic activator can be electron deficient nitrobenzene moieties, electron deficient nitrobenzoic acid amide moieties, nitroazole moieties, nitroimidazole moieties, nitrothiophene moieties, nitrothiazole moieties, nitrooxazole moieties, nitrofuran moieties, and nitropyrrole moieties.
  • the hypoxic activator is a substituted or unsubstituted nitroimidazole moiety.
  • hypoxic activator is selected from:
  • each X 2 is N or CR 32 ;
  • X 3 is NR 31 , S, or O;
  • each R 30 is independently hydrogen or alkyl
  • R 31 is hydrogen, hydroxyl, C 1 -C 6 alkyl or heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aryl or heteroaryl, C 1 -C 6 acyl or heteroacyl, aroyl, or heteroaroyl;
  • R 32 is hydrogen, halogen, nitro, cyano, CO 2 H, C 1 -C 6 alkyl or heteroalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aryl, CON(R 7 ) 2 , C 1 -C 6 acyl or heteroacyl, or aroyl or heteroaroyl; and
  • n 0, 1.
  • Hyp is selected from
  • Hyp is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • tubulin binding compounds can be derivatized to yield prodrugs having the following structures
  • these derivatized compounds in general are less active or inactive compared to the parent compound yielding a hypoxia activated prodrug compound.
  • the prodrug compounds demonstrate a 5-1000 fold loss of anticancer activity upon derivatization with respect to the starting compound.
  • activity data can be obtained from described structure activity relationship data, and via search tools such as SciFinder from the American Chemical Society, Beilstein from MDL Software, US Patent and Trademark Office's Patent and Patent Application search, and European Patent Office's Patent search.
  • the present invention provides compounds of formulas (I)-(VIII):
  • each Q 1 , Q 2 , and Q 6 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 15 ; SO 2 R 15 ; or PO 3 R 15 ;
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 or PO 3 R 15 with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl;
  • Q 7 is hydrogen; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 15 ; SO 2 R 18 ; PO 3 R 18 or a monosaccharide; with the proviso that in formula (II) Q 7 excludes hydrogen;
  • Q 8 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 or PO 3 R 18 ;
  • each Q 9 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 or PO 3 R 18 ;
  • X is O, —NNHR 16 , or NR 16 , or NOR 16 ;
  • Y is hydrogen, hydroxyl, or halogen
  • Z is —CH— or —N—
  • R 15 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • R 16 is hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, C 1 -C 6 alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 acyl, aroyl, aminothiocarbonyl, C 1 -C 6 alkylaminothiocarbonyl, di C 1 -C 6 alkylaminothiocarbonyl, C 1 -C 6 thioacyl, or thioaroyl; with the proviso that when X is NR 16 , R 16 excludes hydrogen;
  • R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • the present invention provides compounds of formulas (I)-(VIII), wherein Q 1 is hydrogen; halo; cyano; nitro; COR 18 ; SO 2 R 18 ; PO 3 R 18 ; ⁇ R 13 or
  • each Q 3 , Q 4 and Q 5 independently is hydrogen, C 1 -C 6 alkoxy, halo, amino, hydroxyl, Q 3 and Q 4 together is methylenedioxy, or Q 4 and Q 5 together is methylenedioxy, provided that in any compound only one of the Q 3 , Q 4 and Q 5 is hydrogen;
  • Q 7 is C 1 -C 6 alkyl optionally substituted independently with one or more aryl, heteroaryl, hydroxyl, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, CO 2 H, or CONH 2 ; COR 18 ; SO 2 R 18 ; or PO 3 R 18 ; or a monosaccharide;
  • each Q 8 and Q 9 is hydrogen
  • R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHCOR 15 , or COR 18 ; and
  • R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides compounds of formulas (I)-(VIII), wherein Q 1 is hydrogen; halo; cyano; CO 2 H; CONH 2 ; ⁇ R 13 ; or ⁇ R 13 ; and each Q 2 -Q 6 independently is hydrogen, C 1 -C 6 , alkoxy; halo; amino; or hydroxy; with the proviso that in any compound only one of the Q 3 , Q 4 , and Q 5 is hydrogen; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides compounds of formulas (I-i), (III-i), (IV-i), (V-i), (VI-i), (VII-i) and (VII-i):
  • X, Y, and Z are defined as above, or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides compounds of formulas (VIII)-(XIII) wherein X is O.
  • the present invention provides the compound of formula:
  • Q 1 is defined as above, or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • Q 1 is
  • the present invention provides the compound of formula:
  • the present invention provides compounds of formulas (IX)-(XIII):
  • R 14 is H, Me, or B(OH) 2 ; and Q1-Q9 are as defined above; or
  • the present invention provides compounds of formula (IX-i)-(XIII-i)
  • R 13 is H, Me, CH 2 OH, CH(Me)OH, CH 2 CH 2 OH, CH 2 NH 2 , CH 2 PO 3 H2, PO 3 H 2 , CO 2 H, or CONH 2 and R 14 is H, Me, or B(OH) 2 ; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of formula (XIV):
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 , or PO 3 R 18 ; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl; with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino; COR 18 or NHCOR 15 ;
  • R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • the present invention provides a compound of formula (XIV), wherein Q 1 is ⁇ R 13 ; or
  • each Q 2 -Q 5 independently is hydrogen, C 1 -C 6 alkoxy; halo; amino; or hydroxy; with the proviso that in any compound only one of the Q 3 , Q 4 and Q 5 is hydrogen; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides compounds selected from:
  • the present invention provides the compound of formula:
  • the present invention provides a compound of formula (XV):
  • each Q 3 , Q 4 , and Q 5 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 ; or PO 3 R 18 with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • Q 7 is hydrogen; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 15 ; SO 2 R 18 ; or PO 3 R 18 or a monosaccharide;
  • R 1 is CH 2 or CO
  • R 3 is hydrogen, halo, C 1 -C 6 alkyl, aryl or heteroaryl;
  • R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino; NHCOR 15 or COR 18 ;
  • R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocyclyl, aryl, or heteroaryl;
  • R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • the present invention provides a compound of formula (XV), wherein each Q 2 -Q 5 independently is hydrogen, C 1 -C 6 , alkoxy; halo; amino; or hydroxy; with the proviso that in any compound only one of the Q 3 , Q 4 and Q 5 is hydrogen; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of formula (XV), wherein R 18 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 cycloalkyl, C 1 -C 6 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • R 18 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 cycloalkyl, C 1 -C 6 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a
  • the present invention provides a compound of formula (XV), wherein Q 1 is
  • the present invention provides a compound of formula (XV), wherein Q 1 is
  • the present invention provides a compound of the formulas (XV-i), (XV-ii) and (XV-iii)
  • Q 2 is C 1 -C 6 alkoxy; and Q 4 is hydrogen or methoxy; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound selected from formulas (XVI)-(XX):
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 ; or PO 3 R 18 with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • Q 6 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 18 ; SO 2 R 18 or PO 3 R 18 ;
  • Q 7 is hydrogen; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 15 ; SO 2 R 18 ; or PO 3 R 18 ; or a monosaccharide;
  • R 5 is hydrogen, halo, or C 1 -C 6 alkoxy
  • R 6 is formyl or a protected form thereof
  • R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHCOR 15 or COR 18 ;
  • R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • R 18 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • the present invention provides a compound selected from formulas (XVI)-(XX), wherein each Q 2 and Q 6 independently is hydrogen, hydroxy, C 1 -C 6 alkoxy, halo, or amino; and each Q 3 , Q 4 , and Q 5 is OMe.
  • Q 2 is hydrogen, hydroxyl, fluoro or methoxy
  • Q 6 is hydrogen, hydroxyl, fluoro, methoxy or amino.
  • the present invention provides a compound selected from formulas (XVI)-(XX), wherein R 18 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 cycloalkyl, C 1 -C 6 heterocyclyl, aryl, or heteroaryl.
  • the present invention provides a compound of formulas (XXI)-(XXVII):
  • each Q 1 , Q 2 , and Q 6 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 18 ; SO 2 R 18 or PO 3 R 18 ;
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 ; or PO 3 R 18 ; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl; with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • Q 7 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 15 ; SO 2 R 18 ; or PO 3 R 18 or a monosaccharide; with the proviso that in formula (II) Q 7 excludes hydrogen;
  • Q 8 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 or PO 3 R 15 ;
  • each Q 9 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 or PO 3 R 15 ;
  • V is —NHR 16 ; —NHNHR 16 ; —NHN(R 16 ) 2 ; —NR 16 NHR 16 ; or —OR 17 ;
  • Y is hydrogen, hydroxyl or halogen
  • Z is —CH— or —N—
  • R 15 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 cycloalkyl, C 1 -C 6 heterocyclyl, aryl, or heteroaryl;
  • R 16 is hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, C 1 -C 6 alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 acyl, aroyl, aminothiocarbonyl, C 1 -C 6 alkylaminothiocarbonyl, di C 1 -C 6 alkylaminothiocarbonyl, C 1 -C 6 thioacyl, or thioaroyl; and R′ is C 1 -C 6 alkyl or aryl; with the proviso that when V is NR 16 , R 16 excludes hydrogen;
  • R 17 is C 1 -C 6 alkyl; aryl; or di C 1 -C 6 alkylamino;
  • R 18 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • the present invention provides a compound of formula (XXI)-(XXVII), wherein Q 1 is hydrogen; halo; cyano; nitro; COR 18 ; SO 2 R 18 ; PO 3 R 18 ; ⁇ R 13 or
  • each Q 3 , Q 4 and Q 5 independently is hydrogen, C 1 -C 6 alkoxy, halo, amino, or hydroxyl provided that in any compound only one of the Q 3 , Q 4 and Q 5 is hydrogen;
  • Q 7 is C 1 -C 6 alkyl optionally substituted independently with one or more aryl, heteroaryl, hydroxyl, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, CO 2 H, or CONH 2 ; COR 18 ; SO 2 R 18 ; or PO 3 R 18 ; or a monosaccharide;
  • R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino; NHCOR 15 or COR 18 ;
  • R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocyclyl, aryl, or heteroaryl;
  • R 16 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, or NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl, NHOH, NHNH 2 , and
  • R 18 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • the present invention provides a compound of formulas (XXI-i), (XXII-i), (XXIII-i), (XXIV-i), (XXV-i) and (XXVII-i):
  • Q 1 , V, Y, and Z is defined as above; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides prodrug compounds as defined above wherein the tubulin binding compound is bonded to the hypoxic activator (Hyp) through an hydroxyloxygen (-OHyp) or an amine nitrogen
  • the hypoxic activator can be electron deficient nitrobenzene moieties, electron deficient nitrobenzoic acid amide moieties, nitroazole moieties, nitroimidazole moieties, nitrothiophene moieties, nitrothiazole moieties, nitrooxazole moieties, nitrofuran moieties, and nitropyrrole moieties.
  • the hypoxic activator is a substituted or unsubstituted nitroimidazole moiety.
  • Hyp is selected from:
  • each X 2 is N or CR 32 ;
  • X 3 is NR 31 , S, or O;
  • each R 30 is independently hydrogen or alkyl
  • R 31 is hydrogen, hydroxyl, C 1 -C 6 alkyl or heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aryl or heteroaryl, C 1 -C 6 acyl or heteroacyl, aroyl, or heteroaroyl;
  • R 32 is hydrogen, halogen, nitro, cyano, CO 2 H, C 1 -C 6 alkyl or heteroalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aryl, CON(R 7 ) 2 , C 1 -C 6 acyl or heteroacyl, or aroyl or heteroaroyl; and
  • n 0, 1.
  • Hyp is selected from
  • Hyp is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention provides compounds of the invention wherein X is —NN(Hyp)R wherein Hyp and R are defined as above.
  • the present invention provides a prodrug of the compound of formula (I-i):
  • the present invention provides a compound of formulas (XXVIII)-(XXXII):
  • each Q 1 , Q 2 , and Q 6 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 18 ; SO 2 R 18 ; or PO 3 R 18 ;
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1-6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 ; or PO 3 R 18 ; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl; with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • Q 8 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 or PO 3 R 15 ;
  • each Q 9 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 or PO 3 R 15 ;
  • V is —NHNHR 16 ; —HNR 16 ; —N(Hyp)NHR 16 ; —NHN(Hyp)R 16 ; or
  • Hyp is a hypoxic activator as defined above;
  • X is O, —NNHR 16 , NR 16 , —NN(Hyp)R 16 , or NOR 16 wherein R 16 is C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, C 1 -C 6 alkoxycarbony, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 acyl, aroyl, aminothiocarbonyl, C 1 -C 6 alkylaminothiocarbonyl, di C 1 -C 6 alkylaminothiocarbonyl, C 1 -C 6 thioacyl, or thioaroyl; with the proviso that when X is NR 16 , R 16 excludes hydrogen;
  • Y is hydrogen, hydroxyl, or halogen
  • Z is —CH— or —N—
  • R 15 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • R 16 is hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, C 1 -C 6 alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 acyl, aroyl, aminothiocarbonyl, C 1 -C 6 alkylaminothiocarbonyl, di C 1 -C 6 alkylaminothiocarbonyl, C 1 -C 6 thioacyl, or thioaroyl; with the proviso that when X is NR 16 , R 16 excludes hydrogen;
  • R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • the present invention provides a compound of formulas (XXVIII)-(XXXII), wherein Q 1 is hydrogen; halo; cyano; nitro; COR 15 ; SO 2 R 15 ; PO 3 R 15 ; ⁇ R 13 or
  • each Q 3 , Q 4 and Q 5 independently is hydrogen, C 1 -C 6 alkoxy, halo, amino, or hydroxylprovided that in any compound only one of the Q3, Q4, and Q 5 is hydrogen;
  • R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino; NHCOR 15 or COR 18 ; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of formula:
  • Q 1 is
  • the present invention provides a compound of selected from the group consisting of:
  • Hyp is as defined above.
  • the present invention provides a compound of formula:
  • Hyp is as defined above.
  • the present invention provides a compound of formula (XIV):
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 , or PO 3 R 18 ; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl; (-OHyp) or (-NHyp) with the proviso that in any one compound, at least one of Q 3 -Q 5 is (-OHyp) or (-NHyp);
  • Q 1 , Q 2 , R 13 , R 15 and Hyp are as defined above; or
  • the present invention provides a compound of formula (XIV), wherein Q 1 is R 13 ; or
  • each Q 2 -Q 5 independently is hydrogen, C 1 -C 6 alkoxy; halo; amino; or hydroxy; with the proviso that in any compound at least one of Q 3 -Q 5 is (-OHyp) or (-NHyp); or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of formula (XXXIV):
  • each Q 3 , Q 4 , and Q 5 independently is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 18 ; SO 2 R 18 ; or PO 3 R 18 ; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl; with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • R 1 is CH 2 or CO
  • R 3 is hydrogen, halo, C 1 -C 6 alkyl, aryl or heteroaryl;
  • R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino; NHCOR 15 or COR 18
  • R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocyclyl, aryl, or heteroaryl;
  • R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • Hyp hypoxic activator
  • the present invention provides a compound of formula (XXXIV-i), (XXXIV-ii) and (XXXIV-iii)
  • Q 2 is C 1 -C 6 alkoxy and Q 4 is hydrogen or methoxy; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of formulas (XXXV)-(XXXIX):
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; heteroaryl; COR 15 ; SO 2 R 15 ; or PO 3 R 15 ; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl; with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • Q 6 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 18 ; SO 2 R 18 or PO 3 R 18 ;
  • Q 7 is hydrogen; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; COR 15 ; SO 2 R 18 ; or PO 3 R 18 ; or a monosaccharide;
  • R 5 is hydrogen, halo, or C 1 -C 6 alkoxy
  • R 6 is formyl or a protected form thereof
  • R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHCOR 15 or COR 15 ;
  • R 15 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • Hyp hypoxic activator
  • the present invention provides prodrug compounds selected from the group consisting of:
  • the present invention provides a compound of formulas (XXXV)-(XXXIX), wherein each Q 2 and Q 6 independently is hydrogen, hydroxy, C 1 -C 6 alkoxy, halo, or amino; and each Q 3 , Q 4 , and Q 5 is OMe.
  • Q 2 is hydrogen, hydroxyl, fluoro or methoxy
  • Q 6 is hydrogen, hydroxyl, fluoro, methoxy or amino
  • R 18 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 cycloalkyl, C 1 -C 6 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of formulas (XL)-(XLIII)
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 ; or PO 3 R 15 with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • Hyp hypoxic activator
  • the present invention provides a compound of formula (XLIV):
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 ; or PO 3 R 15 with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • R 9 is C 1 -C 6 alkyl; aryl; or heteroaryl;
  • R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or
  • R 9 is:
  • the present invention provides a compound of formula (XLV):
  • each Q 3 -Q 5 is hydrogen; halo; amino; C 1 -C 6 alkylamino; di C 1 -C 6 alkylamino; hydroxyl; C 1 -C 6 alkoxy; nitro; cyano; aryl; heteroaryl; COR 15 ; SO 2 R 15 ; or PO 3 R 15 ; Q 3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl; with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
  • R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
  • Hyp hypoxic activator
  • each Q 3 -Q 5 is OMe.
  • the present invention provides a compound of formula (XLVI):
  • R 10 is C 1 -C 6 alkyl and Hyp is hypoxic activator; and a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • R 10 is methyl.
  • the present invention provides the prodrug compound of formula (XLVII):
  • R 11 is methoxy or methyl and each R 12 is halogen, methoxy, methyl, nitro, or amino;
  • Hyp is defined as above; and a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of formula (I)-(XLVII), wherein Q 1 is
  • the present invention provides a compound of formula (I)-(XLVII), wherein Q 1 is
  • the present invention further includes all salts thereof, and particularly, pharmaceutically acceptable salts thereof.
  • the invention includes compounds that are single isomers of the above formula (e.g., single enantiomers of compounds having a single chiral center), as well as solvate, hydrate, a prodrug and tautomeric forms thereof.
  • isomers include single geometric isomers such as cis, trans, E and Z forms of compounds with geometric isomers, or single tautomers of compounds having two or more tautomers.
  • the present invention provides prodrug compounds selected from the group consisting of:
  • Hyp is defined as above; and a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides the following compounds:
  • R is a group which undergoes a tumor specific release such as triggering under hypoxic conditions and R′ ⁇ NH 2 , OH, Cl, F, and Br
  • the present invention provides novel prodrug compounds of the following tubulin binders:
  • each —NH— or OH moiety in a structure above is replaced with —N(Hyp)- wherein Hyp is defined as above.
  • one —NH-moiety in each structure is replaced with —N(Hyp)-.
  • two of those are replaced with —N(Hyp)-.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a novel compound or a novel prodrug compound of the invention.
  • the present invention provides a method of treating cancer comprising administering a therapeutically effective amount of a novel compound or a novel prodrug compound of the invention alone or in combination with one or more other anti-cancer agents to a subject in need of such treatment.
  • the present invention provides a method of treating a hyperproliferative disease comprising administering a therapeutically effective amount of a novel compound or a novel prodrug compound of the invention to a subject in need of such treatment.
  • examples of compounds of the present invention include but are not limited to the following compounds:
  • compounds 9, 10, 11, 14, 21, 22, 30, 35-45, 52-61, 64-72, and 76-81 are bonded through a hydroxyloxygen or an amine nitrogen to a hypoxic activator (Hyp) to provide a hypoxically activated prodrug having (-OHyp) or (-NHyp).
  • a hypoxic activator Hyp
  • the compounds and prodrugs suited for use in the invention are tubulin binding compounds when administered to a human, non-human primate, or other mammal.
  • a compound e.g., a tubulin binding compound
  • Active forms can be identified by routine screening of the compounds of the invention for the activity.
  • assays and tests can be used to assess pharmacological activity of a compound or novel prodrug of the invention, including in vitro assays, such as those described below and elsewhere herein, in vivo assays in humans, non-human primates and other mammals, and/or clinical studies.
  • a tubulin binding compound with similar apoptosis-inducing activity similar to that of Combretastatin A-4 phosphate is selected.
  • a topoisomerase inhibitor that induces apoptosis in cancer cells such as H460, PC3, CCRF, LNCaP, HT29, MESSA and PWR-1E is administered to treat cancer.
  • a tubulin binding compound with similar apoptosis-inducing activity similar to that of Combretastatin A-4 phosphate is selected.
  • a tubulin binding compound that induces apoptosis in skin, epithelial or endothelial, nerve, and T cells is administered to treat a hyperproliferative disease, e.g. psoriasis, rheumatoid arthritis, restenosis, benign prostatic hyperplasia, and multiple sclerosis.
  • the present invention provides a compound of formula (I-VII) having a GI 50 , GI 90 , IC 50 , or IC 50 of about 0.001 to about 1000 nM, about 0.01 to about 100 nm, about 0.1 to about 50 nM, and about 1 to about 10 nM in a cancer cell antiproliferation assay.
  • the present invention provides a compound of formula (I) having a GI 50 or IC 50 of about 0.01 to about 100 nm, about 0.1 to about 50 nm, and about 1 to about 10 nm in a cancer cell antiproliferation assay.
  • said antiproliferation assays employ cancer cell including but not limited to gastric, colon, breast, and non-small cell lung cancer.
  • the gastric cancer cell used is MESSA or doxorubicin resistant MESSA/DX5 cell;
  • the colon cancer cell is HT29 cell;
  • the breast cancer cell is T47D cell; and
  • the non-small cell lung cancer cell is H460 cell.
  • the present invention provides a compound having a GI 50 or IC 50 of about 1 to about 50 nM in a cancer cell antiproliferation assay, such as, for example, compounds 30, 37, 39, 54, 55, 66, 68, 70, 71, and 72.
  • a tubulin binding compound having an IC 50 of tubulin polymerization of about 0.1 to about 10 ⁇ M as determined in a tubulin polymerization inhibition assay, such as for example, compounds 30 and 39.
  • the present invention provides a compound which when subjected to a liver microsomal stability study, remains about 10 to about 100, about 20 to about 80, about 80 to about 100% unmetabolized.
  • the liver microsomal study is conducted for between 10-60, 20-40, or 25-35 minutes.
  • mouse liver microsome is employed in the study. Examples of compounds remaining 80-100% unchanged in a mouse liver microsomal stability study include but are not limited to, compounds 30, 60, 66, and 70.
  • the present invention provides a compound which when subjected to a plasma stability study, remains about 10-100, 20-80, or 80-100% unmetabolized.
  • the plasma stability study is conducted for between 10-60, 20-40, or 25-35 minutes.
  • the plasma employed is from the same species of mammal the liver of whch is employed in the liver microsomal stability study. Examples of compounds remaining 80-100% unchanged in a mouse plasma stability study include but are not limited to, compounds 30, 35, 70, 71, and 72.
  • the present invention provides a compound which upon administration to a human cancer cell xenograft tumor bearing mice, can reduce the tumor volume to about 5-70% of a control tumor volume.
  • the compound is of formula (I)-(XLVII).
  • the compound is of formula (I-VII).
  • the human cancer cell used is H460 cell.
  • the compound administered is of formula (I).
  • An example of a compound useful in reducing mice xenograft tumor is compound 30.
  • the present invention provides a pharmaceutically acceptable formulation of the compounds of the invention, wherein the pharmaceutically acceptable carrier, dilutent, or excipient is selected from a polyethylene glycol (PEG).
  • the pharmaceutically acceptable formulation comprises a compound of formula (I)-(XLVII).
  • the pharmaceutically acceptable formulation comprises a compound of formula (I)-(VIII).
  • the pharmaceutically acceptable formulation comprises a compound of formula (I).
  • Compound 30, for example, can be formulated with a PEG to yield a pharmaceutically acceptable formulation.
  • the present invention provides novel methods for the synthesis of the compounds of this invention.
  • Prodrug compounds of this invention can be synthesized using the novel compounds of the invention and known tubulin binding as described herein as starting material.
  • Known tubulin binding compounds and methods of their synthesis are described, for example, in the references, Martino et al., J. Med. Chem., 2004, ASAP articles; Mahboobi et al., J. Med. Chem. 2001, 44, 4535-53; Gastper et al. J. Med. Chem., 1998, 49, 4965-72; Bacher et al., Pure Appl.
  • the present invention provides a method for synthesizing a compound of the present invention comprising the steps of
  • step (iii) optionally reducing product-2 obtained in step (ii) to yield the compound or prodrug of the invention.
  • step (i) is performed by employing N-halosuccinimide.
  • step (ii) is performed by further employing a Cu(0); a Pd(II); Pd(0) based catalyst.
  • step (ii) is performed by employing a Sonogashira coupling.
  • methods for the synthesis of the compounds of this invention can be identified in accordance with the present invention via search tools such as SciFinder from the American Chemical Society and Beilstein from MDL Software.
  • search tools such as SciFinder from the American Chemical Society and Beilstein from MDL Software.
  • Illustrative methods for making anti-cancer compounds of the present invention in accordance with this disclosure are provided in the EXAMPLES section below.
  • a compound of the present invention disclosed herein is usually formulated as a pharmaceutical composition comprising the compounds or the prodrugs of this invention and a pharmaceutically-acceptable carrier.
  • pharmaceutically acceptable carrier is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.
  • Pharmaceutical preparations for oral use can be obtained through combining active compounds with solid excipient and, optionally, other compounds.
  • Pharmaceutical formulations suitable for parenteral administration can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the dose, schedule and duration of administration of the compound and/or prodrug of the invention will depend on a variety of factors.
  • the primary factor is the choice of a specific compound or prodrug of the present invention.
  • Other important factors include the age, weight and health of the subject, the severity of symptoms, if any, the subject's medical history, co-treatments, goal (e.g., prophylaxis or prevention of relapse), preferred mode of administration of the drug, the formulation used, patient response to the drug, and the like.
  • a compound and/or a prodrug of the invention can be administered at a dose in the range of about 0.1 mg to about 500 mg of a compound and/or prodrug of the invention per kg of body weight of the patient to be treated per day, optionally with more than one dosage unit being administered per day, and typically with the daily dose being administered on multiple consecutive days.
  • the compounds of the present invention include novel compounds of the invention, novel prodrug thereof, and novel prodrugs of known compounds.
  • a compound and/or a prodrug of the invention is administered in a daily dose in the range of about 0.5 mg to about 400 mg/Kg; about 1.0 mg to about 300 mg/Kg; about 1.5 mg to about 250 mg/Kg; about 2.0 mg to about 200 mg/Kg; about 2.5 mg to about 150 mg/Kg; about 5 to about 100 mg/Kg; about 10 to about 50 mg/Kg; and about 10 to about 70 mg per kg of body weight of the patient to be treated.
  • a therapeutically or prophylactically effective dose of a compound and/or a prodrug of the invention can be administered daily or once every other day or once a week to the patient. Controlled and sustained release formulations of the analogs can be used. Generally, multiple administrations of the compound and/or prodrug of the invention are employed. For optimum treatment benefit, the administration of the prophylactically effective dose can be continued for multiple days, such as for at least five consecutive days, and often for at least a week and often for several weeks or more.
  • the compound and/or prodrug of the invention is administered once (qday), twice (bid), three times (tid), or four times (qid) a day or once every other day (qod) or once a week (qweek), and treatment is continued for a period ranging from three days to two weeks or longer.
  • the present invention provides a method for treating cancer or other hyperproliferative diseases by administering to a patient in need of therapy thereof a therapeutically effective dose of a compound or prodrug compound of the invention. In one embodiment, the present invention provides a method for treating cancer or other hyperproliferative diseases by administering about 0.1 to about 500 mg/Kg of a compound or a prodrug compound of the invention to a patient in need of therapy thereof.
  • a compound and/or a prodrug of the invention is administered in a daily dose in the range of about 0.5 mg to about 400 mg/Kg; about 1.0 mg to about 300 mg/Kg; about 1.5 mg to about 250 mg/Kg; about 2.0 mg to about 200 mg/Kg; about 2.5 mg to about 150 mg/Kg; about 5 to about 100 mg/Kg; about 10 to about 50 mg/Kg; and about 10 to about 70 mg per kg of body weight of the patient to be treated.
  • the present invention provides a unit dosage form of about 1 to about 200 mg of a compound or prodrug compound of the invention to a patient in need of therapy thereof.
  • Combretastatin A-4 phosphate CA4P
  • a tubulin-binding compound is reported to have a maximum tolerated daily dose of 60-68 mg/m 2 , and has, for example, been administered to patients in clinical trials in daily doses of 27 and 36 mg/m 2 , by a 10-minute infusion, once every 21 days (Young et al., 2004, Expert Opin. Investig. Drugs, 13(9):1171-82 and Bilenker et al., 2005, Clin. Cancer Res., 11(4):1527-33).
  • the compounds of the present invention can be administered in similar daily doses for treatment of cancer.
  • a compound of the present invention can be administered in a therapeutically affective daily dose of about 10 to about 100 mg/m 2 , about 20 to about 80 mg/m 2 , about 30 to about 70 mg/m 2 , about 40 to about 60 mg/m 2 , and about 45 to about 55 mg/m 2 to treat cancer.
  • a dose in mg/m 2 can be converted to a mg/kg dose in adult humans by dividing the mg/m 2 dose by a factor of 37; in children the corresponding dividing factor is 25.
  • a compound of the present invention can be administered in a therapeutically affective daily dose of about 0.3 to about 3 mg/kg, about 0.6 to about 2.4 mg/kg, about 0.9 to about 2.1 mg/kg, about 1.2 to about 1.8 mg/kg, and about 1.4 to about 1.6 mg/kg to treat cancer.
  • novel compounds of the present invention and the prodrug compounds of the invention can be used in such therapies either in addition to or in substitution of one or more of the co-administered drugs.
  • co-administering a prodrug of the invention with one or more other drugs that target normoxic cells can, in one embodiment of the invention, co-administering a prodrug of the invention with one or more other drugs that target normoxic cells.
  • the hyperproliferative disease is selected from the group consisting of angiofibroma, atherosclerosis, benign prostatic hyperplasia, corneal graft rejection, gout, graft versus host disease, glaucoma, inflammatory diseases such as inflammatory bowel disease, ischemic heart and peripheral vascular disease, Karposi's sarcoma, keloids, life threatening infantile hemangiomas, macular degeration, myocardial angiogenesis, myocardial infraction, multiple sclerosis, neovascular-based dermatological conditions, Osler-Webber Syndrome, osteoarthritis, psoriasis, psoriatic arthritis, pulmonary fibrosis, psoriasis, rheumatoid arthritis, restenosis, rheumatoid arthritis, scleroderma, telangectasia, and wound granularization.
  • angiofibroma atherosclerosis
  • benign prostatic hyperplasia corneal graf
  • a compound and/or a prodrug compound of the invention can be co-administered in combination with other anti-cancer agents (“anticancer agent”).
  • anticancer agent an anti-cancer agent
  • co-administration can in some cases provide one or more of several advantages over known cancer therapies, such as, for example co-administration of a compound and/or a prodrug compound of the invention and the anticancer agent has a synergistic effect on induction of cancer cell death.
  • Co-administration provides a better therapeutic result than administration of the anticancer agent alone, e.g., greater alleviation or amelioration of one or more symptoms of the cancer, diminishment of extent of disease, delay or slowing of disease progression, amelioration, palliation or stabilization of the disease state, partial or complete remission, prolonged survival or other beneficial therapeutic results.
  • the co-administration of a compound and/or a prodrug compound compound of the invention increases the sensitivity of cancer cells to the anticancer agent, allowing lower doses of the anticancer agent to be administered to the patient or allowing an anticancer agent to be used for treatment of cells otherwise resistant to the anticancer agent or otherwise refractory to treatment.
  • anti-cancer agents target rapidly dividing cells in the normoxic region
  • the prodrug compounds of the invention target the hypoxic cells in the regions of tumors that are not efficiently killed by the anticancer agent alone.
  • a compound and/or a prodrug compound of the invention is “co-administered” with another anticancer agent (also referred to herein as, “Agent”) wherein a compound and/or a prodrug compound of the invention and Agent are administered as part of the same course of therapy.
  • Agent another anticancer agent
  • a compound and/or a prodrug compound of the invention is first administered prior to administration of the Agent, (i.e., the initiation of the other cancer therapy), and treatment with the compound and/or prodrug compound of the invention is continued throughout the course of administration of the Agent (i.e., the course of the other therapy).
  • a compound and/or a prodrug compound of the invention is administered after the initiation or completion of the other cancer therapy. In other embodiments, a compound and/or a prodrug compound of the invention is first administered contemporaneously with the initiation of the other cancer therapy.
  • a compound and/or a prodrug compound of the invention is first administered prior to administration of the Agent, and treatment with the compound and/or prodrug compound of the invention is continued after the cessation of administration of the Agent.
  • a compound and/or a prodrug compound of the invention is first administered prior to administration of the Agent, and treatment with the compound and/or prodrug compound of the invention is continued during part of the period of administration of the Agent.
  • administration of a compound and/or a prodrug compound of the invention can be initiated and completed prior to the administration of the second drug.
  • the present invention provides a method wherein a compound and/or a prodrug compound of the invention administered in combination with a chemoprotective agent or a chemoprotectant.
  • Chemoprotective agents protect healthy tissue from the toxic effects of anticancer drugs.
  • the chemoprotective agent is a thiol or a disulfide.
  • the chemoprotectant can reduce superoxide.
  • the chemoprotectant can react with the “Michael-receptor” generated from a hypoxia activated prodrug of the invention and prevent “Michael-receptor” from reacting with proteins and nucleic acid.
  • Anticancer drug therapy today typically involves multiple rounds, or “cycles,” of administration of the anti-cancer agent(s).
  • each cycle of administration (as well as a complete set of cycles) can be viewed as administration of a second drug.
  • a compound and/or a prodrug compound of the invention can be administered in any or all of the multiple cycles of treatment with the other Agent; in general, the compound and/or prodrug compound of the invention is administered on a daily basis for at least two or more days during each cycle.
  • a compound and/or a prodrug compound of the invention is co-administered with the Agent according to a schedule repeated at each round.
  • the compound and/or prodrug compound of the invention is administered in combination with an effective amount of one or more chemotherapeutic agents, an effective amount of radiotherapy, an appropriate surgery procedure, or any combination of such additional therapies.
  • the compound and/or prodrug compound of the invention and additional therapy can be administered at the same time or can be administered separately.
  • the two agents can be administered simultaneously or can be administered sequentially with some time between administrations.
  • One of skill in the art will understand methods of administering the agents simultaneously and sequentially and possible time periods between administrations.
  • the Agents can be administered as the same or different formulations and can be administered via the same or different routes.
  • Chemotherapeutic agents that can be used in combination with the compound of the invention include, but are not limited to, busulfan, improsulfan, piposulfan, benzodepa, carboquone, 2-deoxy-D-glucose, lonidamine and analogs thereof (refrence apps), glufosfamide, meturedepa, uredepa, altretamine, imatinib, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, estramustine, ifosfamide, gefitinib, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, nimustine, ranimustine, dacarbazin
  • a compound and/or a prodrug compound of the invention can be used in combination with an angiogenesis inhibitor including but not limited to Avastin and similar therapeutics.
  • an angiogenesis inhibitor including but not limited to Avastin and similar therapeutics.
  • a subject is treated with an angiogenisis inhibitor and subsequently treated with a compound and/or a prodrug compound of the invention.
  • the method is used to treat breast cancer.
  • a compound and/or a prodrug compound of the invention is administered with an anti-cancer agent that acts, either directly or indirectly, to inhibit the epidermal growth factor or EGFR receptor.
  • EGFR inhibitors suitable for coadministration with a compound of the invention include gefitinib and erlotonib.
  • a compound and/or a prodrug compound of the invention is administered with an anti-cancer agent that acts, either directly or indirectly, to inhibit hypoxia-inducible factor 1 alpha (HIF1a) or to inhibit a protein or enzyme, such as a glucose transporter or VEGF, whose expression or activity is increased upon increased HIF1a levels.
  • an anti-cancer agent that acts, either directly or indirectly, to inhibit hypoxia-inducible factor 1 alpha (HIF1a) or to inhibit a protein or enzyme, such as a glucose transporter or VEGF, whose expression or activity is increased upon increased HIF1a levels.
  • HIF1a inhibitors suitable for use in this version of the methods and compositions described herein include P13 kinase inhibitors; LY294002; rapamycin; histone deacetylase inhibitors such as [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone (FR901228, depsipeptide); heat shock protein 90 (Hsp9) inhibitors such as geldanamycin, 17-allylamino-geldanamycin (17-MG), and other geldanamycin analogs, and radicicol and radicicol derivatives such as KF58333; genistein; indanone; staurosporin; protein kinase-1 (MEK-
  • a compound and/or a prodrug compound of the invention is administered with an anti-angiogenic agent, including but not limited to anti-angiogenic agents selected from the group consisting of angiostatin, an agent that inhibits or otherwise antagonizes the action of VEGF, batimastat, captopril, cartilage derived inhibitor, genistein, endostatin, interleukin, lavendustin A, medroxypregesterone acetate, recombinant human platelet factor 4, Taxol, tecogalan, thalidomide, thrombospondin, TNP-470, and Avastin.
  • an anti-angiogenic agent selected from the group consisting of angiostatin, an agent that inhibits or otherwise antagonizes the action of VEGF, batimastat, captopril, cartilage derived inhibitor, genistein, endostatin, interleukin, lavendustin A, medroxypregesterone acetate, recomb
  • angiogenesis inhibitors for purposes of the combination therapies provided by the present methods and compositions described herein include Cox-2 inhibitors like celecoxib (Celebrex), diclofenac (Voltaren), etodolac (Lodine), fenoprofen (Nalfon), indomethacin (Indocin), ketoprofen (Orudis, Oruvail), ketoralac (Toradol), oxaprozin (Daypro), nabumetone (Relafen), sulindac (Clinoril), tolmetin (Tolectin), rofecoxib (Vioxx), ibuprofen (Advil), naproxen (Aleve, Naprosyn), aspirin, and acetaminophen (Tylenol).
  • Cox-2 inhibitors like celecoxib (Celebrex), diclofenac (Voltaren), etodolac (Lodine), fenoprofen
  • pyruvate mimics and glycolytic inhibitors like halopyruvates, including bromopyruvate can be used in combination with an anti-angiogenic compound and a compound and/or a prodrug compound of the invention to treat cancer.
  • a compound and/or a prodrug compound of the invention is administered with an anti-angiogenic agent and another anti-cancer agent, including but not limited to a cytotoxic agent selected from the group consisting of alkylators, Cisplatin, Carboplatin, and inhibitors of microtubule assembly, to treat cancer.
  • the present methods and compositions described herein provides a variety of synergistic combinations of the compound and/or prodrug compound of the invention and other anti-cancer drugs.
  • Those of skill in the art can readily determine the anti-cancer drugs that act “synergistically” with a compound and/or a prodrug compound of the invention as described herein.
  • the present invention provides a method of cancer treatment, wherein there is synergy between a compound and/or a prodrug compound of the invention and another anticancer agent.
  • Two drugs can be said to possess therapeutic synergy if a combination dose regimen of the two drugs produces a significantly better tumor cell kill than the sum of the single Agents at optimal or maximum tolerated doses.
  • the “degree of synergy” can be defined as net log of tumor cell kill by the optimum combination regimen minus net log of tumor cell kill by the optimal dose of the most active single Agent. Differences in cell kill of greater than ten-fold (one log) are considered conclusively indicative of therapeutic synergy.
  • the compound and/or prodrug compound of the invention When a compound and/or a prodrug compound of the invention is used with another anti-cancer agent, the compound and/or prodrug compound of the invention will, at least in some versions, be administered prior to the initiation of therapy with the other drug or drugs and administration will typically be continued throughout the course of treatment with the other drug or drugs. In some versions, the drug co-administered with a compound and/or a prodrug compound of the invention will be delivered at a lower dose, and optionally for longer periods, than would be the case in the absence of administering the compound and/or prodrug of the invention.
  • Such “low dose” therapies can involve, for example, administering an anti-cancer drug, including but not limited to paclitaxel, docetaxel, doxorubicin, cisplatin, or carboplatin, at a lower than approved dose and for a longer period of time together with a compound and/or a prodrug compound of the invention administered in accordance with the methods described herein.
  • an anti-cancer drug including but not limited to paclitaxel, docetaxel, doxorubicin, cisplatin, or carboplatin
  • the other anti-cancer agent or agents will be administered at the same dose levels used when a compound and/or a prodrug compound of the invention is not co-administered.
  • the additional anti-cancer agent(s) is dosed using either the standard dosages employed for those Agents when used without the compound and/or prodrug compound of the invention or are less than those standard dosages.
  • a compound and/or a prodrug compound of the invention in accordance with the methods described herein can therefore allow the physician to treat cancer with existing (or later approved) drugs at lower doses (than currently used), thus ameliorating some or all of the toxic side effects of such drugs.
  • the exact dosage for a given patient varies from patient to patient, depending on a number of factors including the drug combination employed, the particular disease being treated, and the condition and prior history of the patient, but can be determined using only the skill of the ordinarily skilled artisan in view of the teachings herein.
  • chemotherapeutic agents or antineoplastic agents i.e., the recommended effective dose
  • physicians are given, for example, in the product descriptions found in the Physician's Desk Reference 2003, (Physicians' Desk Reference, 57th Ed) Medical Economics Company, Inc., Oradell, N.J. and/or are available from the Federal Drug Administration.
  • Illustrative dosage regimens for certain anti-cancer drugs are also provided below.
  • Cancer drugs can be classified generally as alkylators, anthracyclines, antibiotics, aromatase inhibitors, bisphosphonates, cyclo-oxygenase inhibitors, estrogen receptor modulators, folate antagonists, inorganic aresenates, microtubule inhibitors, modifiers, nitrosoureas, nucleoside analogs, osteoclast inhibitors, platinum containing compounds, retinoids, topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, and tyrosine kinase inhibitors.
  • a compound and/or a prodrug compound of the invention can be co-administered with any anti-cancer drug from any of these classes or can be administered prior to or after treatment with any such drug or combination of such drugs.
  • a compound and/or a prodrug compound of the invention can be administered in combination with a biologic therapy (e.g., treatment with interferons, interleukins, colony stimulating factors and monoclonal antibodies).
  • Biologics used for treatment of cancer are known in the art and include, for example, trastuzumab (Herceptin), tositumomab and 131 I Tositumomab (Bexxar), rituximab (Rituxan).
  • Alkylators useful in the practice of the methods described herein include but are not limited to busulfan (Myleran, Busulfex), chlorambucil (Leukeran), ifosfamide (with or without MES NA), cyclophosphamide (Cytoxan, Neosar), glufosfamide, melphalan, L-PAM (Alkeran), dacarbazine (DTIC-Dome), and temozolamide (Temodar).
  • a compound and/or a prodrug compound of the invention is co-administered with an alkylator to treat cancer.
  • the cancer is chronic myelogenous leukemia, multiple myeloma, or anaplastic astrocytoma.
  • the present invention provides a method of treating cancer treatable by administering a compound and/or a prodrug compound of the invention alone or in combination with at least another alkylator or a prodrug thereof.
  • Alkylators such as, for example, cyclophosphamide, ifosfamide, glufosfamide, mechlorethamine, melphalan, chlorambucil, dacarbazine, temozolomide, carmustine, streptozocin, bendamustin, busulfan, thiotepa, cisplatin, carboplatin, and oxaliplatin, and types of cancers treated using any one of such alkylators alone or in combination with other anti cancer or chemoprotective agents are described for example in the reference Hardman et al., (see Hardman et al., The Pharmacological Basis of Therapeutics, 2001, 1389-1399, McGraw-Hill, New York, USA).
  • the present invention provides a method of treating cancer by administering a compound and/or a prodrug compound of the invention with a cancer treatment regimen using at least the alkylator Glufosfamide.
  • Glufosfamide is in the clinic for the treatment of pancreatic cancer or Gemzar resistant pancreatic cancer.
  • Glufosfamide can be used for treating breast cancer, Morbus Hodgkin, gastrointestinal tract cancer, or as part of the GCE (Glufosfamide, Carboplatin, and Etoposide) or RGCE (Rituxan and GCE) regimen, for treating lymphomas.
  • GCE Glufosfamide, Carboplatin, and Etoposide
  • RGCE Renuxan and GCE
  • Additional examples of Agents include Terciva, Iressa, Cytarabine and Erbitux.
  • the present invention provides a method of treating cancer by administering a compound and/or a prodrug compound of the invention with a cancer treatment regimen using at least a platinum coordination complex alkylator.
  • the platinum coordination complex alkylator is Cisplatin.
  • Cisplatin can be used to treat cancer of bladder, head and neck, endometrium, small cell carcinoma of the lung, and some neoplasms of childhood.
  • Cisplatin alone or with cyclophosphamide is used to treat advanced ovarian cancer.
  • Combination chemotherapy of Cisplatin with Bleomycin, Etoposide, and Vinblastine is used to treat advanced testicular cancer; and with one of Paclitaxel, Cyclophosphamide, or Doxorubicin to treat ovarian carcinoma.
  • Anthracyclines useful in the practice of the methods described herein include but are not limited to, doxorubicin (Adriamycin, Doxil, Rubex), mitoxantrone (Novantrone), idarubicin (Idamycin), vairubicin (Valstar), and epirubicin (Ellence).
  • doxorubicin Adriamycin, Doxil, Rubex
  • mitoxantrone Novantrone
  • idarubicin Idamycin
  • vairubicin valstar
  • epirubicin Ellence
  • a compound and/or a prodrug compound of the invention is co-administered with an anthracycline to treat cancer.
  • the cancer is acute nonlymphocytic leukemia, Kaposi's sarcoma, prostate cancer, bladder cancer, metastatic carcinoma of the ovary, and breast cancer.
  • the compound (8S,10S)-10-[(3-Amino-2,3,6-trideoxy-alpha.-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione, more commonly known as doxorubicin, is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius .
  • Doxorubicin has been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, lymphomas of both Hodgkin and non-Hodgkin types, bronchogenic carcinoma, and gastric carcinoma.
  • Doxorubicin is typically administered in a dose in the range of 30-75 mg/m 2 as a single intravenous injection administered at 21-day intervals; weekly intravenous injection at doses of 20 mg/m 2 ; or 30 mg/m 2 doses on each of three successive days repeated every four weeks.
  • a compound and/or a prodrug compound of the invention is co-administered starting prior to and continuing after the administration of doxorubicin at such doses (or at lower doses).
  • Cyclic Anthracycline cytotoxin prodrugs useful in the practice of the methods described herein are provided by the reference Matteuci et al., PCT Patent Aplication No. US05/08161.
  • Antibiotics useful in the practice of the methods described herein include but are not limited to dactinomycin, actinomycin D (Cosmegen), bleomycin (Blenoxane), daunorubicin, and daunomycin (Cerubidine, DanuoXome).
  • a compound and/or a prodrug compound of the invention is co-administered with an antibiotic to treat cancer.
  • the cancer is a cancer selected from the group consisting of acute lymphocytic leukemia, other leukemias, and Kaposi's sarcoma.
  • Aromatase inhibitors useful in the practice of the methods described herein include but are not limited to anastrozole (Arimidex) and letroazole (Femara).
  • a compound and/or a prodrug compound of the invention is co-administered with an aromatase inhibitor to treat cancer.
  • the cancer is breast cancer.
  • Bisphosphonate inhibitors useful in the practice of the methods described herein include but are not limited to zoledronate (Zometa).
  • a compound and/or a prodrug compound of the invention is co-administered with a biphosphonate inhibitor to treat cancer.
  • the cancer is a cancer selected from the group consisting of multiple myeloma, bone metastases from solid tumors, or prostate cancer.
  • Cyclo-oxygenase inhibitors useful in the practice of the methods described herein include but are not limited to celecoxib (Celebrex).
  • a compound and/or a prodrug compound of the invention is co-administered with a cyclo-oxygenase inhibitor to treat cancer.
  • the cancer is colon cancer or a pre-cancerous condition known as familial adenomatous polyposis.
  • Estrogen receptor modulators useful in the practice of the methods described herein include but are not limited to tamoxifen (Nolvadex) and fulvestrant (Faslodex).
  • a compound and/or a prodrug compound of the invention is co-administered with an estrogen receptor modulator to treat cancer.
  • the cancer is breast cancer or the treatment is administered to prevent the occurrence or reoccurrence of breast cancer.
  • Folate antagonists useful in the practice of the methods described herein include but are not limited to methotrexate and tremetrexate.
  • a compound and/or a prodrug compound of the invention is co-administered with a folate antagonist to treat cancer.
  • the cancer is osteosarcoma.
  • the compound N-[4-[[(2,4-diamino-6-pteridinyl)methyl methylamino]benzoyl]-L-glutamic acid is an antifolate drug that has been used in the treatment of gestational choriocarcinoma and in the treatment of patients with chorioadenoma destruens and hydatiform mole. It is also useful in the treatment of advanced stages of malignant lymphoma and in the treatment of advanced cases of mycosis fungoides. Methotrexate is administered as follows.
  • intramuscular injections of doses of 15 to 30 mg are administered daily for a five-day course, such courses repeated as needed with rest period of one or more weeks interposed between courses of therapy.
  • twice weekly intramuscular injections are administered in doses of 30 mg/m 2 .
  • weekly intramuscular injections of doses of 50 mg or, alternatively, of 25 mg are administered twice weekly.
  • a compound and/or a prodrug compound of the invention is co-administered with methotrexate administered at such doses (or at lower doses).
  • 5-Methyl-6-[[(3,4,5-trimethoxyphenyl)-amino]methyl]-2,4-quinazolined iamine (commonly known as trimetrexate) is another antifolate drug that can be co-administered with a compound and/or a prodrug compound of the invention.
  • Inorganic arsenates useful in the practice of the methods described herein include but are not limited to arsenic trioxide (Trisenox).
  • Trisenox arsenic trioxide
  • a compound and/or a prodrug compound of the invention is co-administered with an inorganic arsenate to treat cancer.
  • the cancer is refractory acute promyelocytic leukemia (APL).
  • Microtubule inhibitors are any agent that interferes with the assembly or disassembly of microtubules
  • a “microtubule inhibitor” is any agent that interferes with the assembly or disassembly of microtubules
  • useful in the practice of the methods described herein include but are not limited to vincristine (Oncovin), vinblastine (Velban), paclitaxel (Taxol, Paxene), vinorelbine (Navelbine), docetaxel (Taxotere), epothilone B or D or a derivative of either, and discodermolide or its derivatives.
  • a compound and/or prodrug of the invention is co-administered with a microtubule inhibitor to treat cancer.
  • the cancer is ovarian cancer, breast cancer, non-small cell lung cancer, Kaposi's sarcoma, and metastatic cancer of breast or ovary origin.
  • the compound 22-oxo-vincaleukoblastine also commonly known as vincristine, is an alkaloid obtained from the common periwinkle plant (Vinca rosea, Linn.) and is useful in the treatment of acute leukemia. It has also been shown to be useful in combination with other oncolytic agents in the treatment of Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, rhabdomyosarcoma, neuroblastoma, and Wilm's tumor.
  • Vincristine is administered in weekly intravenous doses of 2 mg/m 2 for children and 1.4 mg/m 2 for adults.
  • a compound and/or prodrug compound of the invention is co-administered with vincristine administered at such doses.
  • a compound and/or prodrug compound of the invention is not administered prior to treatment with a microtubule inhibitor, such as a taxane, but rather, administration of a compound and/or prodrug compound of the invention is administered simultaneously with or within a few days to a week after initiation of treatment with a microtubule inhibitor.
  • Modifiers useful in the practice of the methods described herein include but are not limited to Leucovorin (Wellcovorin), which is used with other drugs such as 5-fluorouracil to treat colorectal cancer.
  • a compound and/or prodrug compound of the invention is co-administered with a modifier and another anti-cancer agent to treat cancer.
  • the cancer is colon cancer.
  • the modifier is a compound that increases the ability of a cell to take up glucose, including but not limited to the compound N-hydroxyurea.
  • N-hydroxyurea has been reported to enhance the ability of a cell to take up 2-deoxyglucose (see the reference Smith et al., 1999, Cancer Letters 141: 85, incorporated herein by reference), and administration of N-hydroxyurea at levels reported to increase 2-deoxyglucose uptake or to treat leukemia together with administration of 2-deoxyglucose and a compound of the invention is one version of the therapeutic methods provided herein.
  • a compound and/or prodrug compound of the invention is co-administered with nitric oxide or a nitric oxide precursor, such as an organic nitrite or a spermineNONOate, to treat cancer, as the lafter compounds stimulate the uptake of glucose.
  • Nitrosoureas useful in the practice of the methods described herein include but are not limited to procarbazine (Matulane), lomustine, CCNU (CeeBU), carmustine (BCNU, BICNU, Gliadel Wafer), and estramustine (Emcyt).
  • a compound and/or prodrug compound and/or prodrug compound of the invention is co-administered with a nitrosourea to treat cancer.
  • the cancer is prostate cancer or glioblastoma, including recurrent glioblastoma multiforme.
  • Nucleoside analogs useful in the practice of the methods described herein include but are not limited to mercaptopurine, 6-MP (Purinethol), fluorouracil, 5-FU (Adrucil), thioguanine, 6-TG (Thioguanine), hydroxyurea (Hydrea), cytarabine (Cytosar-U, DepoCyt), floxuridine (FUDR), fludarabine (Fludara), azacytidine (Vidaza), pentostatin (Nipent), cladribine (Leustatin, 2-CdA), gemcitabine (Gemzar), and capecitabine (Xeloda).
  • a compound and/or prodrug compound of the invention is co-administered with a nucleoside analog to treat cancer.
  • the cancer is B-cell lymphocytic leukemia (CLL), hairy cell leukemia, adenocarcinoma of the pancreas, metastatic breast cancer, non-small cell lung cancer, or metastatic colorectal carcinoma.
  • CLL B-cell lymphocytic leukemia
  • hairy cell leukemia adenocarcinoma of the pancreas
  • metastatic breast cancer non-small cell lung cancer
  • non-small cell lung cancer or metastatic colorectal carcinoma.
  • the compound 5-fluoro-2,4(1H,3H)-pyrimidinedione is an antimetabolite nucleoside analog effective in the palliative management of carcinoma of the colon, rectum, breast, stomach, and pancreas in patients who are considered incurable by surgical or other means.
  • 5-Fluorouracil is administered in initial therapy in doses of 12 mg/m 2 given intravenously once daily for 4 successive days with the daily dose not exceeding 800 mg. If no toxicity is observed at any time during the course of the therapy, 6 mg/kg are given intravenously on the 6th, 8th, 10th, and 12th days. No therapy is given on the 5th, 7th, 9th, or 11th days.
  • a daily dose of 6 mg/kg is administered for three days, with the daily dose not exceeding 400 mg. If no toxicity is observed at any time during the treatment, 3 mg/kg can be given on the 5th, 7th, and 9th days. No therapy is given on the 4th, 6th, or 8th days. A sequence of injections on either schedule constitutes a course of therapy.
  • a compound and/or prodrug compound of the invention is co-administered with 5-FU administered at such doses or with the prodrug form Xeloda with correspondingly adjusted doses.
  • the compound 2-amino-1,7-dihydro-6H-purine-6-thione is a nucleoside analog effective in the therapy of acute non-pymphocytic leukemias.
  • 6-Thioguanine is orally administered in doses of about 2 mg/kg of body weight per day. The total daily dose can be given at one time. If after four weeks of dosage at this level there is no improvement, the dosage can be cautiously increased to 3 mg/kg/day.
  • a compound and/or prodrug compound of the invention is co-administered with 6-TG administered at such doses (or at lower doses).
  • Osteoclast inhibitors useful in the practice of the methods described herein include but are not limited to pamidronate (Aredia).
  • a compound and/or prodrug compound of the invention is co-administered with an osteoclast inhibitor to treat cancer.
  • the cancer is osteolytic bone metastases of breast cancer, and one or more additional anti-cancer agents are also co-administered with a compound and/or prodrug compound of the invention.
  • Platinum compounds useful in the practice of the methods described herein include but are not limited to cisplatin (Platinol) and carboplatin (Paraplatin).
  • a compound and/or prodrug compound of the invention is co-administered with a platinum compound to treat cancer.
  • the cancer is metastatic testicular cancer, metastatic ovarian cancer, ovarian carcinoma, and transitional cell bladder cancer.
  • the compound cis-Diaminedichloroplatinum (II) commonly known as cisplatin, is useful in the palliative treatment of metastatic testicular and ovarian tumors, and for the treatment of transitional cell bladder cancer which is not amenable to surgery or radiotherapy.
  • Cisplatin when used for advanced bladder cancer, is administered in intravenous injections of doses of 50-70 mg/m 2 once every three to four weeks.
  • a compound and/or prodrug compound of the invention is co-administered with cisplatin administered at these doses (or at lower doses).
  • One or more additional anti-cancer agents can be co-administered with the platinum compound and a compound and/or prodrug compound of the invention.
  • Platinol, Blenoxane, and Velbam can be co-administered with a compound and/or a prodrug compound of the invention.
  • Platinol and Adriamycin can be co-administered with a compound and/or a prodrug compound of the invention.
  • Retinoids useful in the practice of the methods described herein include but are not limited to tretinoin, ATRA (Vesanoid), alitretinoin (Panretin), and bexarotene (Targretin).
  • a compound and/or a prodrug compound of the invention is co-administered with a retinoid to treat cancer.
  • the cancer is a cancer selected from the group consisting of APL, Kaposi's sarcoma, and T-cell lymphoma.
  • Topoisomerase 1 inhibitors useful in the practice of the methods described herein include but are not limited to topotecan (Hycamtin) and irinotecan (Camptostar).
  • a compound and/or a prodrug compound of the invention is co-administered with a topoisomerase 1 inhibitor to treat cancer.
  • Topoisomerase inhibitors and prodrugs thereof useful in the practice of the methods of the present invention are provided in the reference Matteucci et al., U.S. Patent Application No. 60/629,723.
  • the cancer is metastatic carcinoma of the ovary, colon, or rectum, or small cell lung cancer.
  • administration of a compound and/or a prodrug compound of the invention either precedes or follows, or both, administration of a topoisomerase 1 inhibitor but is not administered concurrently therewith.
  • Topoisomerase 2 inhibitors useful in the practice of the methods described herein include but are not limited to etoposide, VP-16 (Vepesid), teniposide, VM-26 (Vumon), and etoposide phosphate (Etopophos).
  • a compound and/or prodrug compound of the invention is co-administered with a topoisomerase 2 inhibitor to treat cancer.
  • the cancer is a cancer selected from the group consisting of refractory testicular tumors, refractory acute lymphoblastic leukemia (ALL), and small cell lung cancer.
  • ALL refractory acute lymphoblastic leukemia
  • small cell lung cancer small cell lung cancer.
  • Tyrosine kinase inhibitors useful in the practice of the methods described herein include but are not limited to imatinib (Gleevec).
  • a compound and/or a prodrug compound of the invention is co-administered with a tyrosine kinase inhibitor to treat cancer.
  • the cancer is CML or a metastatic or unresectable malignant gastrointestinal stromal tumor.
  • a compound and/or a prodrug compound of the invention or a pharmaceutically acceptable salt thereof and one or more additional anti-cancer agents are administered to a patient.
  • additional anti-cancer agents include without limitation 5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]-methyl]-2,4-quinazolinediamine or a pharmaceutically acceptable salt thereof, (8S,10S)-10-(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione or a pharmaceutically acceptable salt thereof; 5-fluoro-2,4(1H,3H)-pyrimidinedione or a pharmaceutically acceptable salt thereof; 2-amino-1,7-dihydro-6H-purine-6
  • Compound 4 can also be prepared by a similar procedure from compound 7 (100 mg, 0.56 mmol), 157 mg 5-iodo-1,2,3-trimethoxybenzene (0.53 mmol), PdCl 2 (PPh 3 ) 2 (19 mg, 5.0 mol %), and CuI (5.1 mg, 5.0 mol %) in TEA (8 mL).
  • Novel prodrugs 14 and 15 of this invention can be synthesized following the procedure described for the synthesis of compounds 12 and 13 by reacting compound 9 with
  • Example 11 provides methods for synthesizing Compound 22 starting from compound 9.
  • Example 12 provides methods for synthesizing Compound 30 starting from compound 22.
  • Example 13 provides a method of synthesizing compounds 54 and 55 starting from compound 30.
  • Example 14 provides a method of synthesizing compound 53.
  • Example 15 provides a method of synthesizing compound 56.
  • Example 16 provides a method of synthesizing compound 57.
  • Example 17 provides a method of synthesizing compounds 58-60.
  • Example 18 provides a method of synthesizing compound 61.
  • Example 19 provides a method of synthesizing compound 61.
  • Example 20 provides a method of synthesizing compound 62-64.
  • Example 21 provides a method of synthesizing compounds 66-71.
  • Example 22 provides a method of synthesizing compounds 73 and 74.
  • Example 23 provides a method of synthesizing compound 75.
  • Example 24 provides a method of synthesizing compound 76.
  • Example 25 provides a method of synthesizing Compound 77.
  • Example 26 provides a method of synthesizing Compound 78.
  • Example 27 provides a method of synthesizing Compound 79.
  • Example 28 provides a method of synthesizing Compound 80.
  • Example 18 provides method for synthesis of novel a prodrug compound of the invention derived from a novel compound of the invention.
  • Example 30 provides method for synthesis of prodrug compounds of the invention employing as starting material a known tubulin binding compounds.
  • Example 31 provides method for synthesis of prodrug compounds of the invention employing as starting material a known tubulin binding compounds.
  • the antiproliferative activity of these compounds was tested in a multi-well Alamar Blue based assay (at 2 h and 3 days). Cell growth in the presence and absence of the test compound as tabulated in Table 1 was compared, as measured by a fluorescence plate reader at excitation 550 nm and emission 590 nm (see Biosource International Inc., Tech Application Notes, Use of Alamar Blue in the measurement of Cell Viability and Toxicity , Determining IC 50 ).
  • H460 cells ATCC HTB-177 (NCI-H40), 4,000 cells/well/200 ⁇ l
  • LNCap cells ATCC CRL-1740, 6,000 cells/well/200 ⁇ l
  • a test compound was added to each plate in the treatment groups (2 h and 3 day) at a concentration as tabulated in Table 1 (in 50 ⁇ l of medium).
  • the cells were rinsed to remove the test compound and incubated for 3 days, followed by staining with AlamarBlue.
  • the cells in the 3-day treatment group were incubated for 3 days, followed by staining with AlamarBlue.
  • AlamarBlue was added to the plate at (i) day 0 and (ii) day 3 and measured to establish the control reading.
  • the capacity of the cells to proliferate was measured 6 hours after addition of AlamarBlue by a fluorescence plate reader at excitation 550 nm and emission 590 nm. The results of the assay are tabulated in Tables 1A and 1B.
  • the effect of compounds 39 and 20 on the cell cycle was determined as follows. H460 cells (2 ⁇ 10 5 cells/ml/well) were seeded in a 24 well plate. After 24 h, compound was added at various concentrations as tabulated in Table 3. The culture media were removed after 24 h, the cells were trypsinized and centrifuged. The cell pellets were resuspended in 100 ⁇ l PBS buffer, after which 300 ⁇ l of ice-cold ethanol (96%) added dropwise, and the cells were incubated at 4° C. for at least 24 hr. The cells were centrifuged and the supernatant was discarded.
  • the cell cycle staining reagent (Guava Technologies, Hayward, Calif., USA, 200 ⁇ l) was added to each well. The cells were shielded from light and incubated at room temperature for 30 min. The samples were analyzed (Guava PCA-96 instrument, Cytosoft software, Guava Technologies, 25801 Industrial Boulevard, Hayward Calif. 94545-2991, USA) to show M phase cell cycle arrest as tabulated below in Table 2.
  • a sample of cell free tubulin polymerizes and the sample's fluorescence emission increases.
  • Inhibition of tubulin polymerization by a tubulin binding compounds of the present invention was measured by the dose dependence of cell free tubulin fluorescence.
  • concentration of compound that reduced tubulin fluorescence by 50% compared to untreated tubulin are tabulated below in Table 3:
  • mice plasma For an assessment of plasma stability of compounds, commercially available mouse plasma (Bioreclamation, Hicksville, N.Y.) was added to a DMSO solution of a compound, to a concentration of 5 ⁇ M. The reaction mixture (50 ⁇ l) was withdrawn immediately and after 30 minutes at 37° C., proteins were precipitated with acetonitrile. The clear supernatant was analyzed by reversed phase LC-MS/MS and the amount the compound remaining quantified as shown in table 4.
  • Example 28 describes the usefulness of a compound of this invention in treating cancer as demonstrated employing a H460 xenograft mouse model.
  • mice Female CB17/SCID mice (purchased from Taconic, Oxnard, Calif.), 7-8 weeks of age, were allowed to acclimatize for at least three days, and handled under pathogen-free conditions.
  • Human non-small cell lung cancer cell line NCI-H60 was obtained from the American Type Culture Collection. The cell lines were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum. Cells were maintained in a 37° C. incubator with 5% CO 2 . The H460 cells were harvested from culture and inoculated at 1 ⁇ 10 6 cells/animal in the peritoneal subcutaneous space.
  • each group of mice (ten per group) was administered for five days, vehicle alone (the vehicle group), compound 30 alone at a daily dose of 5, 20, and 50 mg/kg (treatment group), and compound 30 alone at a daily dose of 5, and 20 mg/kg in combination with Taxol® at a daily dose of 10 mg/kg (combination group). Taxol was administered approximately 2-3 hours before that of compound 30.
  • Compound 30, administered at doses greater than 5 mg/kg were toxic and caused lethality in both treatment and combination groups perhaps indicating that the maximum tolerated dose of compound 30 was between 5 and 20 mg/kg.
  • the results from the experiment employing a daily dose compound 30 (5 mg/kg) are shown graphically in FIGS. 1 and 2 below.
  • the body weight of each mouse was recorded twice per week ( FIG. 1 ).
  • the treatment group administered a daily dose of 5 mg/kg exhibited a weight pattern similar to that of the vehicle group with a mean weight loss of 8% on day 22 from the start of treatment on day 8.
  • Animals in the combination group displayed a weight loss of 13%.
  • One animal in the treatment group was found dead on day 18, and two were found dead on day 22 in the combination group.
  • the TIC for day 21 was 56%.
  • the xenograft data for compound 30 demonstrates that compared to the known anticancer agent taxol, compound 30 can show in vivo anti tumor activity both as a single agent and in combination with taxol.

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WO2006057946A3 (fr) 2007-07-05
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MX2007006102A (es) 2007-07-11
JP2008520719A (ja) 2008-06-19
WO2006057946A2 (fr) 2006-06-01
KR20070086595A (ko) 2007-08-27
NO20073211L (no) 2007-08-21
CA2587210A1 (fr) 2006-06-01
IL183212A0 (en) 2008-04-13
AU2005309761A1 (en) 2006-06-01

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